The Phosphinamide-Based Catalysts: Discovery, Methodology Development, and Applications in Natural Product Synthesis.

In the total synthesis of natural products, synthetic efficiency has been an important driver for designing and developing new synthetic strategies and methodologies. To this end, the step, atom, and time economy and the overall yield are major factors to be considered. On the other hand, developing unified routes that can be used for synthesizing multiple molecules, specifically skeletally different classes of molecules, are also important aspects with which to be concerned. In the efforts toward efficient and flexible synthesis of structurally unique terpenoid and indole alkaloid natural products, we have designed and developed several phosphinamide-based new catalysts and reaction methodologies that have been compellingly demonstrated to be widely useful as strategic protocols for the diverse synthesis of various complex terpenoids and indole alkaloids. The important progress of these results will be summarized in this Account.In the first part, we present the stories of successful design and establishment of a novel method for the synthesis of P-stereogenic phosphinamides (P-SPhos) via a Pd-catalyzed C-H desymmetric enantioselective arylation, as well as the flexible derivatization of the P-stereogenic phosphinamides into various types of skeletally unique tricyclic and N,P-bidentate P-stereogenic compounds. Subsequently, the discovery of P-stereogenic phosphinamides as chiral organocatalysts for the desymmetric enantioselective reduction of cyclic 1,3-diketones and of phosphinamide-based cyclopalladium complex (C-Pd) as precatalysts for highly efficient Suzuki-Miyaura cross-coupling reaction of sterically congested nonactivated enolates is introduced. The notable features of the P-stereogenic phosphinamide-catalyzed desymmetric enantioselective reduction are highlighted by the broad substrate compatibility and excellent stereoselectivity, as well as most significantly, the good recoverability and reusability of catalysts. With regard to the sterically congested nonactivated enolates, such substrates are challenging for Suzuki cross-coupling reactions. We demonstrate that the phosphinamide-based cyclopalladium is a type of highly active precatalyst that allows the reaction to proceed under mild conditions and to be easily scaled up. Following the methodology development, the practical applications of these methods serving as strategic transformations are highlighted by the unified synthesis of four cyathane-type and two hamigeran-type terpenoids.In the second part, we describe the development of a robust method for oxidative Heck cross-coupling of indolyl amides by using the phosphinamide-based cyclopalladium as catalyst or phosphinamide as coligand. The method provides a general and straightforward method for diverse synthesis of indolyl δ-lactam derivatives, which present as a common core in a variety of Aspidosperma-derived indole alkaloids. The successful demonstration of this protocol for a concise and divergent synthesis of leuconodine-type indole alkaloids is also presented. We believe the results presented in this Account would have significant implications beyond our results and would find further applications in the field of synthetic methodology and natural product synthesis.

A Divergent Enantioselective Total Synthesis of Post-Iboga Indole Alkaloids.

Divergent enantioselective total syntheses of five naturally occurring post-iboga indole alkaloids, dippinine B and C, 10,11-demethoxychippiine, 3-O-methyl-10,11-demethoxychippiine, and 3-hydroxy-3,4-secocoronaridine, as well as the two analogues 11-demethoxydippinine A and D, are presented for the first time. The enantioenriched aza[3.3.1]-bridged cycle, a common core intermediate to the target molecules, was constructed through an asymmetric phase-transfer-catalyzed Michael/aldol cascade reaction. The challenging azepane ring fused around the indole ring and the [3.3.1]-bridged cycle were installed through an intramolecular SN 2'-type reaction. These cyclization strategies enabled rapid construction of the [6.5.6.6.7]-pentacyclic core at an early stage. Highlights of the late-stage synthetic steps include a Pd-catalyzed Stille coupling and a highly stereoselective catalyst-controlled hydrogenation to incorporate the side chain at C20 with both R and S configurations in the natural products.

Enantioselective Total Synthesis and Absolute Configuration Assignment of (+)-Tronocarpine Enabled by an Asymmetric Michael/Aldol Reaction.

We present the first asymmetric total synthesis and absolute configuration determination of (+)-tronocarpine. The [6.5.7.6.6] pentacyclic core was constructed at an early stage by using a sequential cyclization strategy through a newly developed catalytic asymmetric Michael/aldol cascade to build the aza[3.3.1]-bridged cycle and a tandem reduction/hemiamidation procedure to assemble the seven-membered lactam. The side-chain functionalities were incorporated at a late stage by several appropriately orchestrated manipulations under mild conditions. The synthesis of enantiomerically pure (+)-tronocarpine was achieved through a 20-step longest linear sequence from tryptamine.

Synthetic Studies on Enantioselective Total Synthesis of Cyathane Diterpenoids: Cyrneines A and B, Glaucopine C, and (+)-Allocyathin B2.

The details for the synthetic studies on enantioselective total synthesis of cyathane diterpenoids cyrneine A (1) and B (2), glaucopine C (3), and (+)-allocyathin B2 are presented. We established a mild Suzuki coupling for heavily substituted nonactivated cyclopentenyl triflates using a phosphinamide-derived palladacycle as precatalyst and a chelation-controlled highly regioselective Friedel-Crafts cyclization. The utilization of these two key reactions enabled a rapid construction of the 5-6-6 tricyclic skeleton. In the middle stage of the synthesis, a Birch reductive methylation, a modified Wolff-Kishner-Huang reduction, and a carbenoid-mediated ring expansion were employed as the key reactions to furnish the 5-6-7 tricyclic core bearing two antiorientated all-carbon quaternary stereocenters at the C6 and C9 ring junctions. By applying these key transformations, a more efficient total synthesis of cyrneine A and allocyathin B2, and the first total synthesis of cyrneine B and glaucopine C, were accomplished through a collective manner. The late-stage conversions involving a base-mediated double bond migration and a double bond migration/aerobic γ-CH oxidation cascade for the stereoselective synthesis of cyrneine B and glaucopine C were interesting.

Greatly Accelerated Condensation of d-Mannose Diacetonide with Aqueous Formaldehyde (Formalin).

Condensation of d-mannose diacetate with aqueous formaldehyde, a long known quaternary center-generating transformation, was reinvestigated to solve the hidden problem of incomplete conversion, a lasting challenge since 1979 despite many previous efforts. The mysterious cause for the retarded transformation was found to be generation of formic acid by a Cannizzaro reaction. By using additional amounts of base, the reaction time was shortened from 48 h to 100 min and the product was readily isolated in 81% yield.

Constructing CoNi-LDH/Fe MOF/NF Heterostructure Catalyst for Energy-Efficient OER and UOR at High Current Density.

The sluggish kinetics of the oxygen evolution reaction (OER) always results in a high overpotential at the anode of water electrolysis and an excessive electric energy consumption, which has been a major obstacle for hydrogen production through water electrolysis. In this study, we present a CoNi-LDH/Fe MOF/NF heterostructure catalyst with nanoneedle array morphology for the OER. In 1.0 M KOH solution, the heterostructure catalyst only required overpotentials of 275 and 305 mV to achieve high current densities of 500 and 1000 mA/cm2 for OER, respectively. The catalytic activities are much higher than those of the reference single-component CoNi-LDH/NF and Fe MOF/NF catalysts. The improved catalytic performance of the heterostructure catalyst can be ascribed to the synergistic effect of CoNi-LDH and Fe MOF. In particular, when the anodic OER is replaced with the urea oxidation reaction (UOR), which has a relatively lower thermodynamic equilibrium potential and is expected to reduce the cell voltage, the overpotentials required to achieve the same current densities can be reduced by 80 and 40 mV, respectively. The cell voltage required to drive overall urea splitting (OUS) is only 1.55 V at 100 mA/cm2 in the Pt/C/NF||CoNi-LDH/Fe MOF/NF two-electrode electrolytic cell. This value is 60 mV lower compared with that required for overall water splitting (OWS). Our results indicate that a reasonable construction of a heterostructure catalyst can significantly give rise to higher electrocatalytic performance, and using UOR to replace the anodic OER of the OWS can greatly reduce the electrolytic energy consumption.

Total synthesis of cyrneines A-B and glaucopine C.

The cyrneine diterpenoids represent a structurally intriguing subfamily of cyathane diterpenoids and could significantly induce neurite outgrowth. Therefore, the efficient synthesis of these natural products is of great importance. Herein, we present a route for the collective synthesis of cyrneines A, B, and glaucopine C. As the key precursor, the 5-6-6-tricyclic scaffold is efficiently constructed by employing a mild Suzuki coupling of heavily substituted nonactivated cyclopentenyl triflate and a chelation-controlled regiospecific Friedel-Crafts cyclization as key transformations. The stereoselective installation of the all-carbon quaternary center at C6 ring junction of the tricycle is achieved via Birch reductive methylation. Subsequently, a carbenoid-mediated ring expansion furnishes the essential 5-6-7-tricyclic core. Finally, manipulation of this core by several appropriately orchestrated conversions accomplishes a more step-economic synthesis of cyrneine A (20 steps), and the first synthesis of cyrneine B (24 steps) and glaucopine C (23 steps).

Synthesis and Structural Reassignment of Plakinidone.

In connection with its first synthesis, plakinidone was structurally revised to a five-membered lactone. The key evidence for the previous assignment of this natural product as a perlactone was proven to be a misinterpretation of the MS data because of unawareness of a facile air oxidation. The synthetic samples also allowed for detection of differences in (13)C NMR for diastereomers of remote stereogenic centers, along with the influence of the air oxidation on the optical rotation.